The human transcriptional positive cofactor 4 (PC4, also known as p14, p15, Sub1 homolog, etc.) is a single-stranded DNA-binding protein of 127-amino acid residues with serine-rich regions near the N-terminus. This cofactor has been cloned and identified as a general positive cofactor that could mediate transcriptional activation of many genes by directly interacting with many sequence- and cell-specific regulators [Ge and Roeder, (1994), Purification, cloning and characterization of a human coactivator, PC4, that mediates transcriptional activation of class II genes. Cell 78, 513-523; Kretzschmar, M. et al., (1994) A novel mediator of class II gene transcription with homology to viral immediate-early transcriptional regulators. Cell 78, 525-534]. The regulators mediated by PC4 include many nuclear hormone receptors, tumor suppressors, onco-proteins and other important factors that are essential for tumorigenesis and pathogenesis of other human diseases.
The expression of PC4 is controlled by the tumor suppressor protein p53, which interacts with the PC4 protein itself at the transcription level. In addition, PC4 functions as a unique activator of p53 to regulate transcription of a number of genes involved in cell cycle, apoptosis, DNA repair and other cellular responses [Kishore A. H. et al., (2007) p53 regulates its own activator-transcriptional coactivator PC4: a new p53 responsive gene. Biochem. J. BJ20070390; Banerjee, S. et al. (2004) General transcriptional coactivator PC4 activates p53 function. Mol. Cell Biol. 24, 2052-2062]. PC4 activities can be further regulated by posttranslational modification at least including phosphorylation and acetylation. Phosphorylation of PC4 inhibits its activity to interact with targeted activators and negatively regulates its co-activator function. Mass spectrometric analyses suggest that the in vivo hyperphosphorylation of PC4 is mainly mediated by casein kinase II and restricted to the N-terminal serine-rich region [Ge, H. et al., (1994) Phosphorylation negatively regulates the function of coactivator PC4. Proc. Natl. Acad. Sci. USA 91, 12691-12695]. Acetylation of PC4 is mediated by p300 and inhibited by phosphorylation [Kumor, P. B. R. et al., (2001) p300-mediated acetylation of human transcriptional coactivator PC4 is inhibited by phosphorylation. J. Biol. Chem. 276, 16804-16809].
The roles of PC4 in regulatory genes related to cancer or tumorigenesis have been heretofore unclear. There is a need for improved molecular diagnosis of malignancy. In addition, there is a need for improved methods of screening for cancer inhibition agents as well as safe and effective cancer inhibition agents with enhanced tumor specificity and reduced toxicity to normal cells and tissues.